Recent work in our laboratory has indicated that a degenerative loss of hypocretin (orexin) neurons underlies most cases of human narcolepsy. Several chronic diseases have symptomatic similarities to narcolepsy. This suggests that they may share abnormalities in the operation of the hypocretin (Hcrt) system. For example, patients with unipolar depression and schizophrenia exhibit REM sleep at sleep onset, one of the defining characteristics of narcolepsy. Nighttime sleep is frequently disrupted in both disorders, as in narcolepsy. The age of onset of both of these disorders is similar to that of narcolepsy. Many patients with schizophrenia have hallucinations resembling the hypnagogic hallucinations of narcolepsy. Alzheimer's disease, like narcolepsy, is characterized by daytime sleepiness and nighttime sleep disruption. This "sundowning" and related hallucinatory mentation is the most frequent cause of institutionalization. We have developed a far more sensitive assay for Hcrt than that used in prior published studies and have access to a large number of cerebrospinal fluid (CSF) samples from these three groups of patients and suitable controls. We will determine if low Hcrt levels are unique to narcolepsy or if they are present in one or more of these other disorders. We will determine if an Hcrt blood test can be developed to detect narcolepsy. Such a test would have an enormous impact upon the diagnosis and treatment of sleep disorders and on sleep research in general. We will compare blood Hcrt levels in narcoleptics, sleep apneics, REM sleep behavior disorder patients and controls. In parallel animal studies, we will determine the effect of behavior, including motor activity, feeding and short term sleep deprivation upon CSF Hcrt levels. Finally, we will use in vivo microdialysis to determine the pattern of Hcrt release in locus coeruleus, hypothalamus and ventrolateral preoptic area across the sleep wake cycle. We will contrast release patterns in active vs. quiet waking and REM vs. nonREM sleep. These studies will help define the role of this newly identified neurotransmitter system in relation to motor behavior, the sleep wake cycle and in human disease.